Project Summary/Abstract An urgent need exists to understand the impact of aging on mucosal immunity in the female reproductive tract (FRT) of postmenopausal women, given the increased risk of infections and the lack of knowledge of immune alterations that occur as women age. Recognizing that menopause and the accompanying absence of sex hormones fundamentally alters the immune environment in the FRT, the overall goal of this proposal is to arrive at a mechanistic understanding of how aging (50-59, 60-69 and >70yrs) impacts pathogen recognition, immune protection and induction of immune responses in the upper and lower FRT. This proposal has 3 original Aims: 1) Determine the extent to which aging compromises immune protection by FRT epithelial cells. As epithelial cells are the first line of defense against pathogens, we will identify the extent to which pattern recognition receptor (PRR) signaling by epithelial cells is compromised with aging. We will also determine age- dependent changes in secreted innate molecules with antimicrobial and chemotaxis capacity. 2) Determine the impact of aging on local immune protection by evaluating resident and non-resident T cell function throughout the FRT. In this Aim, we will evaluate age-dependent changes in cytotoxic activity and secreted immune responses (antimicrobials and cytokines) following activation of CD4+ and CD8+ tissue resident and non-resident T cells throughout the FRT. 3) Determine the impact of aging on dendritic cell (DC) pathogen recognition and induction of T cell responses throughout the FRT. This aim will identify age-associated changes in PRR responses by DCs and in DC's ability to induce T cell responses, as well as the mechanisms that control DC function as women age. This study is unique in that it integrates aging with our understanding of the innate and adaptive mucosal immune system throughout the human FRT, as it relates directly to mucosal protection by the very cells most likely to interact and respond to pathogens. These studies will provide much needed information that is essential to identify age-related changes in immune function in the FRT and influence responses to urinary tract infections (UTIs) and sexually-transmitted infections (STIs). As older women are generally excluded from prevention research for STIs, and vaccination recommendations (for example HPV), our studies will provide a foundation to define mucosal immune protection in elderly women and develop appropriate strategies for the prevention of new infections and pathogen reactivation.